Cystic fibrosis (CF) is the most common life-shortening genetic disorder in Caucasians with approximately 70,000 people affected worldwide. CF is a multisystem disease affecting the respiratory tract, the digestive system and the genito-urinary system. The major focus of treatment is the respiratory tract since, by age 24, nearly 80% of patients with CF have chronic Pseudomonas aeruginosa (PA) airway infection, which is associated with an accelerated decline in pulmonary function and is a significant predictor of mortality (2005 Annual Data Report to the Center Directors, Bethesda, Md., Cystic Fibrosis Foundation, Bethesda, Md. 2006; Pamukcu, A, Pediatr. Pulmonol. 1995; 19:10-5; Henry, R L, Pediatr. Pulmonol. 1992; 12:158-61).
Clinical management of CF has improved during the past 15 years. Increased standardization of care and a focus on maintenance therapies, including nutrition, combined with the introduction of dornase alfa in 1993, tobramycin inhalation solution (TIS)(TOBI®) in 1998, and widespread use of chronic azithromycin during the past five years have been associated with approximately an 8-year increase in median predicted survival age (to 36.5 years; 1990-2005) and an increase in median forced expiratory volume in 1 second (FEV1) percent predicted of approximately 10% across all age groups (1990-2005)(Clement, A, Thorax 2006; 61:895-902; Gibson, R L, Am. J. Respir. Crit. Care Med. 2003; 168:918-51).
Conventional measures of clinical improvement in CF, such as FEV1 and bacterial sputum density, that are directed exclusively to respiratory effects of the treatments, do not capture the broader impact of CF on a patient's physical, social, and emotional functioning and may also miss the effects of treatment on other systems that may be affected by the disease. These additional aspects of many lung diseases are measured with health-related quality-of-life (HRQOL) instruments that have been developed for CF, asthma, and other lung diseases (Chang, J A, Chest 1999, 116, 1175-1182; Juniper, E, Am. Rev. Respir. Dis., 1993, 147, 832-838; Henry, B, Qual. Life Res., 2003, 12, 63-76). These measurements reflect an individual's subjective evaluation of his or her daily functioning and well-being, i.e., patient centered evaluation rather than physician centered evaluation. In chronic diseases, some treatments may produce benefits in activities of daily living that are not reflected in conventional medical measurements. For instance, clinical interventions to increase calorie intake to produce changes in weight and height in young children may increase energy levels and the ability to participate in sports in some individuals. Such an outcome is often more exciting for the families than simple weight or height gains. A patient's perception of improvements in daily functioning may also increase adherence to complex and time-consuming treatment regimens for some individuals. In addition, HRQOL instruments provide a basis for evaluating the effectiveness of treatments that are time-consuming and use significant health care resources. This latter effect is important for comparing the cost-effectiveness of different treatments that can influence access to the treatments and reimbursement policies for the treatments. Therefore, there is a need to develop drugs that improve the scores of the HRQOL in patients with lung diseases irrespective of the conventional clinical measurements that may be differentially affected by treatment with the same or a different drug.
Effects on quality-of-life symptoms of CF can be measured with HRQOL instruments such as the CF Questionnaire-Revised (CFQ-R) (Quittner, Chest 2005, 128, 2347-2354). Disease-related quality-of-life symptoms of CF include eating and digestive disturbances, emotional and physical dysfunction, diminished health perceptions, respiratory disturbances, role/school dysfunction, diminished vitality, diminished social functioning, diminished weight, and other measures of quality of life such as increased treatment burden. These disease-related symptoms are of particularly relevance for patients with CF, who must adhere to complex, time-consuming medical regimens that affect their normal activities. Their perception of treatment benefit is likely to improve adherence to treatment regimens and influence their long-term health outcomes as measured by conventional clinical measurements as well as improve the cost effectiveness of their treatment choices (Modi, A C, Pediatr. Pulmonol. 2005; S28:371). Therefore, there is a need for therapies that generally improve the scores of the HRQOL of CF patients.
Aztreonam lysine for inhalation (AZLI) is a dry powder or aerosolized formulation of the monobactam antibiotic, aztreonam, and lysine (Montgomery, U.S. Pat. Nos. 6,660,249, 7,138,419, 7208,141, 7,214,364, U.S. patent application Ser. Nos. 11/732,234 and 11/729,698; each of which is incorporated by reference in their entirety). In the clinic, AZLI improved the clinical symptoms of CF including FEV1 sputum Pseudomonas aeruginosa concentrations and the time to need for inhaled or intravenous antibiotics (Gilead press releases, Dec. 19, 2006 and Apr. 19, 2007; McCoy, K.; et al., 30th European Cystic Fibrosis Conference Jun. 13-16, 2007, Poster 40, Antalya, Turkey).